2-149576487-C-G

Variant names:

• chr2-149576487-C-G
• NM_015702.3:c.428G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015702.3(MMADHC):​c.428G>C​(p.Ser143Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S143I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MMADHC NM_015702.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.533

Genes affected

MMADHC (HGNC:25221): (metabolism of cobalamin associated D) This gene encodes a mitochondrial protein that is involved in an early step of vitamin B12 metabolism. Vitamin B12 (cobalamin) is essential for normal development and survival in humans. Mutations in this gene cause methylmalonic aciduria and homocystinuria type cblD (MMADHC), a disorder of cobalamin metabolism that is characterized by decreased levels of the coenzymes adenosylcobalamin and methylcobalamin. Pseudogenes have been identified on chromosomes 11 and X.[provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10464513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMADHC	NM_015702.3	c.428G>C	p.Ser143Thr	missense_variant	Exon 5 of 8	ENST00000303319.10	NP_056517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMADHC	ENST00000303319.10	c.428G>C	p.Ser143Thr	missense_variant	Exon 5 of 8	1	NM_015702.3	ENSP00000301920.5
MMADHC	ENST00000422782.2	c.428G>C	p.Ser143Thr	missense_variant	Exon 5 of 9	5		ENSP00000408331.2
MMADHC	ENST00000428879.5	c.428G>C	p.Ser143Thr	missense_variant	Exon 4 of 7	2		ENSP00000389060.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461384 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	.;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.81	L;L;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.90	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.64	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.12
MutPred		0.36		Gain of relative solvent accessibility (P = 0.1066);Gain of relative solvent accessibility (P = 0.1066);Gain of relative solvent accessibility (P = 0.1066);
MVP		0.63
MPC		0.032
ClinPred		0.23	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-150433001;